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D.A. Cameron (United Kingdom)

David Cameron looks at data on HER2+ breast cancer, where the discovery of the importance of the HER2 protein in breast cancer has revolutionized the treatment of patients with this disease. The presentation also covers some of the unmet needs.

Transcription

I’m going to look really at data on HER2+ breast cancer where of course the discovery of the importance of the HER2 protein in breast cancer has revolutionised the treatment for patients with this disease. We have four licensed compounds; trastuzumab, pertuzumab, lapatinib and T-DM1.

Full transcription

Full transcription

I’m going to look really at data on HER2+ breast cancer where of course the discovery of the importance of the HER2 protein in breast cancer has revolutionised the treatment for patients with this disease. We have four licensed compounds; trastuzumab, pertuzumab, lapatinib and T-DM1.

I am going to point to some of the unmet needs, but I’ll say now two areas which I will not cover, mostly for reasons of time. The first is whether the menopausal status of the patient, influences how we treat them?

We know it matters for endocrine therapy. We actually don’t have much data as to whether it should influence the way we combine endocrine therapy with HER2-positive disease and the other really important area of course is the treatment of CNS disease which is a big, big unmet need in this patient group and again we don’t have an awful lot of data. Although some of the smaller molecules have reported some activity and some new drugs coming through to be tested.

So I am telling you now – those two areas I won’t look at but I will try and cover briefly some of the key questions, a little bit on the biology and some of the background data as well as of course the clinical data that influences our practice.

Dislosures

Disclosures.

Disclaimers

Disclaimers – I will mention a whole lot of ‘ibs’. Don’t ask me to pronounce them, I can’t. This will come in at the end of the talk as we look for the future direction of other ways to overcome emergent resistance. None of these drugs of course are licensed for use, they are all in clinical trial testing in various parts of the world.

Factors Affecting Treatment Decisions in Advanced Breast Cancer

When we sit as a clinician with a patient with advanced breast cancer, there are a lot of factors that influence our decision about how to treat her, or occasionally him.

Two really important pieces of information that come from the pathologist are the HER2 status and the hormone receptor status and I will talk about that.

The other really important thing of course is patient preference, but actually clinical decision-making is based on a number of other factors, too; previous therapies, the clinical data on drugs, disease-free interval, tumour burden, performance status, how quickly we have to get shrinkage, psychological, sociological, financial, chronological factors – all of these go into the mix.

Unfortunately we have to extract the data on those from clinical trials. We tend to not do trials addressing some of these more complex factors and we need to bear that in mind as we come to clinical decision-making.

Ultimately we also need to consider what clinical trials are available, but of course that depends on which country and in which hospital you are sitting in, so we can’t really talk about that as driving choice for an individual patient.

Factors Affecting Treatment Decisions in Advanced Breast Cancer

Perhaps two of the most important are these two and I will focus on the first one but it’s not to ignore the second one. We will look at some of the toxicity data which may sometimes influence a patient’s choice.

HER2 and HR Crosstalk

Now it’s not a coincidence that we’ve pulled out HER2 and the HR pathway. Not only do they drive drug selection thinking, but actually inside the cancer cells in our patients, they drive the cell biology and as many of you know, there is biological interaction between them so that the two pathways crosstalk.

So that’s your ER pathway, it will drive gene expression but both at the cell surface and at an interaction here, these two pathways talk to each other so that we have to think about both not just for treatment selection but actually understanding the biology of the cancer.

Current Treatment Algorithm: HER2+ Metastatic Breast Cancer

For the patients whose cancers don’t have hormone receptors but are HER2+, the choice is essentially HER2-directed therapy and chemotherapy.

In the first-line setting, it’s essentially combining HER2 therapy with chemotherapy. Whether or not you can give pertuzumab is primarily driven by access to the drug; for example where I work I actually can’t get pertuzumab for financial reasons and I know I’m not alone in the world.

But nevertheless, this is an important consideration but beyond that, the choices are more multiple. When a patient unfortunately does progress on their first-line HER2 therapy we have a number of choices. The most effective drug from randomised trials is T-DM1 but you have an oral combination of lapatinib and capecitabine, there are other combinations you can do off-label as well as on-label. You have a doublet, lapatinib and trastuzumab and of course you can continue your first-line anti-HER2 therapy and switch to a different cytotoxic agent.

For the younger people in the room, when the pivotal trial was done with this, that actually obviously without trastuzumab, was one of the options even back in the late 1990s. The concept of carrying on with an anti-HER2 agent has been around a long time.

Current Treatment Algorithm: HER2+ Metastatic Breast Cancer

For the women who have hormone receptors as well as HER2 over-expression, we essentially have a different first choice. Do you go down the chemo plus HER2 route or do you go down the hormone therapy route, in which case you have a second question; do you give endocrine therapy on its own or do you combine it with anti-HER2 therapy?

Once they progress which sadly the vast majority do, clearly the chemotherapy route simply follows what’s on option over there but in the endocrine therapy route, do you switch endocrine therapy, do you add in HER2 therapy if you haven’t given it and so on?

So the pathways start to get very complicated and the clinical trials actually don’t always tell us the optimum sequence.

HER2-targeted Therapy + Chemotherapy: Any HR Status

In the first-line setting, the most convincing and most effective combination is pertuzumab, trastuzumab and docetaxel. You know these data; a six-month increase in progression-free survival and a 16-month increase in overall survival. Very powerful effects.

In terms of toxicity, most toxicities are the same but there is more diarrhoea and so there may be some patients for whom that additional risk of diarrhoea is unacceptable.

HER2-targeted Therapy: Any HR Status

In the second-line setting, the most powerful data came through from T-DM1 and this is the comparison between T-DM1 and capecitabine/lapatinib with 9.5 versus 6.5 months and associated with that an improvement in overall survival.

The toxicity of these two approaches is quite different. For many of them, like PPE – that’s a hand-foot syndrome – diarrhoea, vomiting they are worse on capetitabine/lapatinib. However, thrombocytopenia and fatigue are actually worse on T-DM1. Again, whilst T-DM1 is more effective as a clinical drug, there may be patients for whom factors other than efficacy are important in terms of tolerability.

HER2-targeted Therapy + Chemotherapy: Any HR Status

In the second-line setting capecitabine/lapatinib was better than capecitabine, which is one of the reasons why it’s there but it does bring some toxicity. Although again not everything is worse. For example, fatigue was worse on the higher dose of capecitabine.

All of these data apply to people with hormone receptor positive and negative cancers. No signal emerging yet that the hormone receptor status influences the efficacy of these anti-HER2 directed therapies.

HER2-targeted Therapy + Endocrine Therapy: HR+ Disease

For those who are HR+ you can combine endocrine therapy using an AI and certainly the randomised data all come through with AIs with either trastuzumab or lapatinib.

There is no question across the different studies that the combination is more effective in terms of PFS, although the most impressive one is actually the smallest of the studies.

However, the crosstalk may matter here. Not only is AI on its own not terribly effective, but actually for example in this study they didn’t get an awful lot more by adding in trastuzumab, so some clinicians prefer to keep the HER2 therapy to combine with chemo.

Dual Blockade of HER2: HR- Disease

Interestingly there are some data that suggest there may be situations where the hormone receptor status does influence how effective the anti-HER2 therapy is.

This is a randomised trial of lapatinib against lapatinib plus trastuzumab in patients who had progressed on prior trastuzumab, often more than one line but that prior trastuzumab was in combination with chemo. Lapatinib on its own is not usually effective in terms of PFS, very similar in the two groups of patients, but in the HR- patients it is almost doubled by adding in lapatinib and that’s associated with an improvement in overall survival.

This combination is licensed in Europe in the hormone receptor negative patients, so a difference there according to the HR status on your cancer.

Importance of Molecular Re-testing

We are learning and we have learnt, that just because a patient’s primary cancer had one particular set of markers, it doesn’t guarantee you that when you treat her or him with metastatic disease the same markers are there.

This summarises four studies which look at the change in status between primary and metastasis. Losing hormone receptors, going from positive to negative, so giving them an endocrine agent would be useless, between 5% and 12%, not insignificant.

Gaining hormone receptor status, almost as great, so for them you have an additional line. So just because they were ER negative at the beginning doesn’t mean they couldn’t switch. You need to re-biopsy to show that.

Loss of HER2 is relatively uncommon, but actually gaining HER2 can again occur in up to 13%. If you don’t re-biopsy your patient who is HER2-, she may have up to a one in ten chance of becoming HER2+, you will never know that and so you won’t give her an additional important armamentarium.

So re-biopsy where it’s safe and appropriate is important to make sure that your therapeutic choices are the right ones for that patient.

Signaling Pathways Downstream of HER2

Now the paradigm of the crosstalk between the hormone receptor and the HR2 receptors doesn’t live in isolation. There are a large number of other biological pathways sitting inside the cancer cells and we’ve picked out a few because they are now enzymes and pathways that we can block therapeutically.

Signaling Pathways Downstream of HER2

That’s important in trying to overcome the resistance which is almost inevitable in our patients with metastatic cancer to a sequence of HER2-directed therapies.

Signaling Pathways Downstream of HER2

Preclinical data suggest activation of the PI3 kinase/mTOR pathway may contribute to such resistance, of course in the clinic there’s data suggesting activation of the pathway is associated with a poor response.

So the proof-of-principle study came from the BOLERO-3 trial where patients who had had prior taxanes with anti-HER2 therapy and had progressed were randomised between the same anti-HER2 therapy, trastuzumab plus a different chemo, vinorelbine with or without everolimus.

Now clinically the improvement in PFS was not dramatic, it was just more than a month but it’s a proof-of-principle in patients who were resistant, although were clearly not refractory to all therapies, adding in everolimus, blocking that pathway can bring additional benefit.

And another hint – and it is only a hint – some difference in sensitivity according to hormone receptor status, but the suggestion that it’s the hormone receptor negative patients where this may be more effective.

Of course adding in an extra drug there are some additional toxicities as you would expect from everolimus such as dermatitis and anaemia.

Signaling Pathways Downstream of HER2

Of course upstream of mTOR there are a number of other enzymes, drivers like AKT and PI3 kinase which feed through mTOR, so this is another area where emerging agents that are not yet licensed but are in clinical trials, could additionally overcome HER2 resistance.

Phase I/II Study of Buparlisib + Trastuzumab

There are some provocative, tantalising data. This is with buparlisib which is a pan-PI3K inhibitor plus trastuzumab in patients who are resistant to trastuzumab. They should see no response to trastuzumab and yet in this Phase I/II study they have two patients who get a partial response and eight who have stable disease, one of them, okay only for six months but a suggestion that this could be another effective therapeutic avenue.

We need the later studies to prove that it’s the best way forward, but it’s encouraging that the preclinical data have some supportive clinical data from this early phase study.

Ongoing Studies of PI3K Inhibitors in HER2+ Breast Cancer

It’s not the only study and it’s not the only drug being tested in this space. I’m not going to read them all out, you can see them. The key point is that these agents are going into clinical trials mostly in Phase I, some into Phase Ib, and it will tell us whether the preclinical data really pan out into something useful in the clinic.

Signaling Pathways Downstream of HER2

The other area where there is emerging research is downstream of mTOR and that’s through CDK4/6 and cyclin D where we have three drugs in clinical development, none licensed in Europe although of course this one is in the US.

Cyclin D is important in ER+ breast cancer and this whole pathway may well be important in resistance to HER2 therapy.

Ongoing Studies of CDK4/6 Inhibitors in HER2+ Breast Cancer

Again as you would expect there are clinical trials in process, Phase I, Phase Ib and Phase II with at least two of these agents. We will see whether this emerging into a clinically useful strategy, but the preclinical data suggests that it may well do and we know from the data from PALOMA-1 and PALOMA-3 that palbociclib is fairly well tolerated in our patients so we don’t expect massive increases in toxicity.

Summary

In summary, identification of HER2 was critically important for dealing with that aggressive and previously harder to treat group of patients with breast cancer but knowledge of the hormone receptor status is also important in driving treatment decisions.

We have a number of EMA approved targeted therapy combinations; pertuzumab, trastuzumab and docetaxel, lapatinib and capecitabine, trastuzumab with an AI, lapatinib with an AI. Obviously both of those are only in HR+ patients and lapatinib and trastuzumab only in patients without hormone receptor statuses.

Upstream and downstream other important biological targets are now being challenged in clinical trials with agents that block PI3 kinase/mTOR and with CDK4/6 and we will see whether these turn out to be useful therapeutic strategies or not.

Thank you. [Applause]

Interim Assessment: Poll and Panel Discussion

Now it’s time for you to do some work. Let’s see if this system works. We have a couple of cases for you to think about and vote on. The voting system works because most of you knew which dance was associated with Vienna. Some of you might have preferred a different one like Flamenco but never mind.

Case Study 1

This is the clinical case first. June 2013 a post-menopausal woman aged 65 was diagnosed with Stage IIB HR- but HER2 over-expressing or positive breast cancer.

She had surgery and went on to get doxorubicin and cyclophosphamide followed by paclitaxel plus trastuzumab.

Can we go back? Unfortunately, as you might have guessed but you weren’t allowed to read because these guys were too efficient, the breast cancer relapsed and she had lung metastases. She then went to get pertuzumab, trastuzumab and docetaxel and as may well happen in an older patient who’s got prior anthracyclines and some anti-HER2 therapy, she had a decrease in LVEF.

She had a break, the pertuzumab/trastuzumab was restarted and her LVEF did not drop again so she could continue with this treatment until April eight months later when she progressed.

At this point she got T-DM1 but unfortunately five months later she again progressed and this time her performance status is starting to drop, so she’s not quite so well now with a performance of two.

Question: Which Treatment Would You Suggest?

So now, what would you do next? Vote now please. These are your four proscribed choices and obviously you have freedom at the end and as I say to all of these, if there is a clinical trial that’s appropriate, that’s obviously on the list. We have not put it up because it’s difficult to define for individuals. Vote now. [Pause for voting]

Okay, so the vast majority of you would give lapatinib which is not unreasonable. She has had trastuzumab, pertuzumab, T-DM1, it’s actually really the only other licensed agent. Some of you want to give it with trastuzumab, which is logical. She is HR-, it’s licensed, it has activity although remember of course that trial was done before T-DM1 was around.

Others of you would give lapatinib plus capecitabine. The same is true of its licence, but again those data we have from the randomised Phase III, patients were not pre-treated with T-DM1, so we don’t know quite what the activity would be, but I think it’s a very logical choice.

But 10% of you want to go back to trastuzumab and add in a different chemotherapy agent. It’s not unreasonable, although in fact we don’t have any data there either and a small group of you want to carry on T-DM1 which I find slightly odd because she’s clearly progressing on it.

I guess the situation could be if she was only progressing in the brain and the rest of the systemic disease was under control, that does make sense, provided she got radiotherapy to the brain or some other treatment there.

And a few of you have some other clever ideas which may be right, but there are a range of other options including trials.

Case Study 2

So the second case study, again go back a year to March, 2014, a post-menopausal woman aged 58, previously fit and well presents with metastatic disease that’s both hormone receptor positive and HER2 positive. She has bone mets and small volume lung mets.

She received trastuzumab and docetaxel, very well tolerated, no cardiac toxicity but like many patients after six cycles of docetaxel she turned to the doctor and said ‘Nah, don’t want any more of that drug, thank you. I’ve had enough of it but please can I carry on with the trastuzumab?’. The clinician felt it was appropriate to add in an AI because she was HR+, so she continued on an AI plus trastuzumab.

Question: Which First-line Treatment Would You Have Chosen?

Now the question is would you have agreed with her first-line therapy? 58, de novo presentation, bone and low volume lung mets; she got chemotherapy plus trastuzumab. Here’s your chance to say that you would have done the same or something different, so vote now. [Pause for voting]

Okay, so just over half of you would have given her pertuzumab, trastuzumab and docetaxel. I think if you opt for chemotherapy and anti-HER2 therapy and you can access both agents, it’s entirely logical; it’s licensed, it’s the most effective combination there.

A quarter of you would have chosen not to give chemotherapy at all but to give her endocrine therapy plus anti-HER2 therapy. I think for bone only disease or bone with small volume disease elsewhere, particularly if it’s small volume in the lung probably picked up on a staging CT, it makes sense.

If she tolerates that and it works, she can get on with her previously fit life. Are we out of time?

Andre: There is a comment on the right.

Cameron: A comment.

Cortés: I would like to ask you and to ask the audience something. So assuming that at least in Europe pertuzumab is only approved in the first-line, so agreed that maybe other strategies could be acceptable, would you not administer pertuzumab if you know that you are not going to be allowed to use it afterwards in second line?

Cameron: I think that drives the question; if you are going to give chemotherapy and anti-HER2 and you can give pertuzumab, that makes sense but if for example you chose to give an AI alone which one or two people in the room would do, you can still go back to docetaxel, pertuzumab, trastuzumab once they have failed endocrine therapy.

I think the challenge of giving trastuzumab plus AI is exactly that, which is would you be then able to give docetaxel, pertuzumab, trastuzumab? I have no idea what the licence says to be quite frank about that. I suspect it wouldn’t be allowed by licence but many institutions may be able to give it.

I think that raises the question of do you keep your anti-HER2 therapy to give with chemo and particularly with pertuzumab available, I think that’s a very valid question, Javier.

Case Study 2

Okay, unfortunately like most patients after about 18 months having had docetaxel, trastuzumab and then AI for a year, she progresses only in bone, so what next?

Question: Which Second-line Treatment Would You Suggest?

So this is your choice - progressed in bone only when she was taking an AI and trastuzumab, having had docetaxel and trastuzumab.

Choose between these and vote now. [Pause for voting]

Very interesting, so the majority of you would continue blocking HER2 and obviously the next logical and most effective second-line strategy would be T-DM1 and I would not criticise that.

Some of you, maybe because you can’t get T-DM1, maybe because you are concerned about something else to do with T-DM1, would continue trastuzumab and add in a different chemotherapy agent. 15% or 16% would give lapatinib/capecitabine. It’s an alternative second-line therapy, it doesn’t require any IV administration.

10% of you want to stop HER2 and presumably change the AI which is interesting. I don’t know whether they are the same people who would have given an AI up-front, but if she only has small progression in bones she may have had enough of IV treatments and chemo. It might be worth trying and you may want to come back to HER2 therapy later if she had a good control.

I think that’s a very interesting range of options. Do either of you want to comment on that? Pertuzumab wasn’t on the list, Javier because it’s as you say not really licensed.

Cortés: In my opinion – this is just my opinion – I don’t like to look at subgroup analyses except for if there is a clear rationale for that. For example BOLERO-1 and BOLERO-3, I really liked to see the ER positive versus ER negative HER2+ disease because it makes sense. Everolimus might work only in the ER- and we do not combine with endocrine therapy, but here it is not the case, so in my opinion and I have exactly the same with pertuzumab therapy, in my opinion to have or not these metastases, that was the opinion, should not be something very, very important to consider T-DM1 or not.

I think that if we do not take into account costs and at least in Europe I think that anti-HER2 therapy, should we administer in second-line and I think that T-DM1 seems to be the most reasonable option if possible and if available in a country.

Cameron: Yes, I don’t disagree with that. I think it’s a very active and appropriate choice but there may be reasons why the patient didn’t want an IV drug, for example. That’s why an oral approach which numbers three and four offer you might have been preferable but it’s the one I would have expected to come out with a majority and it makes sense to me.

Right – Fabrice, over to you.

Andre: First maybe are there any questions in the room? Remember you can submit questions on the iPad.

Cortés: I have a question for David. Having the data of EMILIA and having the data of THERESA do you think –?

Andre: Can you remind us exactly what are the data of these beautiful names?

Cortés: That’s why I pronounce carefully. Do you think there is room to delay the use of T-DM1 to third-line or beyond if you can use it in second-line? I’m talking in general.

Cameron: I think given the data we have, it is the most active second-line effective therapy. I think if you are going to use it and have access to it, it makes sense to give it in second-line.

To give it in third-line what would you want, to give it after? Would that be chemotherapy plus another one or two anti-HER2 agents like pertuzumab, trastuzumab? We have no data.

I think the challenge is if a patient for whatever reason declined it, said to you ‘I don’t want an IV drug. I’m going to sail around the world, give me my tablets’, then it’s not inappropriate to try it but based on the data we have, second-line seems to be the right place to use it.

Cortés: I have one more comment. Sorry – it’s the last one. In clinical practice, which is the disease-free interval you consider to use T-DM1 in first-line in trastuzumab pre-treated patients versus pertuzumab in first-line? According to the clinical trials, EMILIA six months, CLEOPATRA more than 12 months, between six and 12 who knows, but in the clinical practice would you recommend?

Cameron: I’ll be honest with you, I don’t have access to T-DM1, I live in a very poor country North of the UK, so I don’t face that problem but I agree with you, we don’t know. My instinct would be if I can get access to pertuzumab I would use that because that’s where all the data are in combination with trastuzumab and chemo which is in the first-line setting. That’s the problem.

T-DM1, all the data really are in second-line apart from those who have had close recurrence, so I don’t think we know what the correct time interval is – that’s the problem.

Andre: Okay, we have one question; I am going to read the question. Given the positive results of everolimus in BOLERO-2, so it’s ER+, HER2- and the BOLERO-3 trial which is HER2+, would you suggest initiation of everolimus before the biopsy result is available? I think the question is about will you wait for HER2 before starting everolimus in patients who are resistant?

I can take the question. The problem with BOLERO-3 is that we need to keep in mind that everolimus has the label in ER+, HER2- who are resistant to aromatase inhibitor, but right now there is no approval for everolimus in HER2+ breast cancer, so I think for the decision to administer everolimus, HER2 is really an important decision criterion.